DESCRIPTION: The long-term goal of this research is twofold: 1) To elucidate the molecular and cellular mechanisms underlying ethanol's effects on the cAMP signaling pathway in the central nervous system, and 2) To determine the role that the cAMP signaling pathway plays in the physiological and behavioral responses to alcohol abuse. The cAMP signal transduction system may play an important role in the development of alcoholism. Several lines of evidence indicate that alcoholic individuals have abnormal cAMP signal transduction and that genetic determinants may contribute to these abnormalities. If a change in cAMP signaling is one of the determinants of an alcoholic phenotype, it is conceivable that alterations in the cAMP signaling system in an animal model may change the animal's response to ethanol. The hypothesis to be evaluated is that the response of animals to ethanol can be altered-by the modification of adenylyl cyclase (AC) expression. To test this hypothesis, transgenic mice that overexpress type VII AC (AC7: the most ethanol sensitive isoform) will be generated. Once changes in the expression of AC7 are confirmed, the ethanol sensitivity of AC activity in the brain of the transgenic mice will be examined. The sensitivity of the transgenic mice to acute ethanol intoxication will be examined by measuring the duration of loss of righting reflex (sleep time) and the changes in body temperature (hypothermia). The proposed studies will generate valuable animal models for alcoholism research. These animals will also be useful for a widerange of physiological and behavioral research dealing with cAMP signal transduction. The proposed studies will also provide information critical to the determination of whether abnormal cAMP signaling is one of the determinants of an alcoholic phenotype.